Article

A Novel Bone Morphogenetic Protein Signaling in Heterotypic Cell Interactions in Prostate Cancer

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Cancer Research (Impact Factor: 9.33). 02/2008; 68(1):198-205. DOI: 10.1158/0008-5472.CAN-07-5074
Source: PubMed

ABSTRACT

We examined the effect of the extracellular bone morphogenetic protein (BMP) 2 and 7, which are up-regulated in the prostate adenocarcinomas of the conditional Pten deletion mouse model, on primary cultures of cancer-associated fibroblasts (CAF) derived from these tumors. In the CAF, we show that BMP2 or BMP7, but not transforming growth factor beta-1, can strikingly stimulate secretion of stromal cell-derived factor-1 (SDF-1), also known as CXCL12. The CAF cells express type I and type II BMP receptors as well as the receptor for SDF-1, CXCR4. SDF-1 activation is associated with BMP-induced Smad phosphorylation, and the stimulatory effect is blocked by BMP antagonist, noggin. The findings that BMP treatment can increase SDF-1 pre-mRNA levels in a time-dependent manner and actinomycin D treatment can abolish stimulatory effect of BMP suggest a transcriptional modulation of SDF-1 by BMP signaling. Using a human microvascular endothelial cell line, we show that SDF-1 present in the conditioned medium from the stimulated CAF can significantly induce tube formation, an effect relating to angiogenic function. Furthermore, we found that BMP2 can also protect the CAF from serum starvation-induced apoptosis independent of SDF-1, implying that BMP may induce other factors to sustain the survival of these cells. In short, this report establishes a novel BMP-SDF-1 axis in the prostate tumor along with a new prosurvival effect of BMP that when considered together with our previously described oncogenic properties of BMP indicate a circuitry for heterotypic cell interactions potentially critical in prostate cancer.

Full-text preview

Available from: cancerres.aacrjournals.org
  • Source
    • "Also, the idea of BMP as a tumor suppressor is consistent with a recent study showing that prostate epithelial specific knock out of SMAD signaling in the conditional Pten prostate cancer model increases aggressiveness of tumor progression and occurrence of metastasis; BMP/transforming growth factor b signaling may actually act as a barrier to metastasis in the mouse model (Ding et al. 2011). As we have evidence that BMP is able to stimulate tumor-promoting properties of CAF cells in vitro (Yang et al. 2008), we also over-expressed noggin in CAF cells of the tumor model to determine their effect on tumor growth induced by either E8 or cE1 cells. We presumed that reconstituting a tumor with these cellular components might recapitulate tumor behavior, at least in part, to that encountered in vivo. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have focused on the impact of bone morphogenetic protein (BMP) on prostate cancer homing and growth at distant metastatic sites, but very little on impact at the primary site. Here we used two cell lines, one (E8) isolated from a primary tumor and the other (cE1) from a recurrent tumor arising at the primary site, both from the conditional Pten deletion mouse model of prostatic adenocarcinoma. Over-expression of the BMP antagonist Noggin inhibited proliferation of cE1 cells in vitro while enhancing their ability to migrate. On the other hand cE1/Noggin grafts grown in vivo showed a greater mass and a higher proliferation index than the cE1/Control grafts. For suppression of BMP activity in the context of cancer associated fibroblasts (CAFs), we used Noggin-transduced CAFs from the same mouse model to determine their effect on E8 or cE1 induced tumor growth. CAF/Noggin led to increased tumor mass and greater de-differentiation of the E8 cell as compared to tumors formed in the presence of CAF/Control cells. A trend in increase in the size of the tumor was also noted for cE1 cells when inoculated with CAF/Noggin. Together, the results may point to a potential inhibitory role of BMP in the growth or re-growth of prostate tumor at the primary site. Additionally, results for cE1/Noggin, and cE1 mixed with CAF/Noggin suggested that suppression of BMP activity in the cancer cells may have a stronger growth enhancing effect on the tumor than its suppression in the fibroblastic compartment of the tumor microenvironment.
    Preview · Article · Sep 2013 · Endocrine Related Cancer
  • Source
    • "We were interested in determining whether this increase may have distinct effects on cells in the tumor stromal microenvironment, which can have paracrine effects on carcinoma cells. Recently, it was discovered that fibroblasts derived from mouse prostate tumors stimulated by BMPs can increase angiogenesis via the upregulation of the chemokine SDF1α/CXCL12 [12]. This finding was supported by earlier work demonstrating that BMPs were playing active roles in the promotion of prostate tumorigenesis and subsequently bone metastases [18], [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone Morphogenetic Proteins (BMPs) are secreted cytokines that are part of the Transforming Growth Factor β (TGFβ) superfamily. BMPs have been shown to be highly expressed in human breast cancers, and loss of BMP signaling in mammary carcinomas has been shown to accelerate metastases. Interestingly, other work has indicated that stimulation of dermal fibroblasts with BMP can enhance secretion of pro-tumorigenic factors. Furthermore, treatment of carcinoma-associated fibroblasts (CAFs) derived from a mouse prostate carcinoma with BMP4 was shown to stimulate angiogenesis. We sought to determine the effect of BMP treatment on mammary fibroblasts. A large number of secreted pro-inflammatory cytokines and matrix-metallo proteases (MMPs) were found to be upregulated in response to BMP4 treatment. Fibroblasts that were stimulated with BMP4 were found to enhance mammary carcinoma cell invasion, and these effects were inhibited by a BMP receptor kinase antagonist. Treatment with BMP in turn elevated pro-tumorigenic secreted factors such as IL-6 and MMP-3. These experiments demonstrate that BMP may stimulate tumor progression within the tumor microenvironment.
    Full-text · Article · Jun 2013 · PLoS ONE
  • Source
    • "However, cancer cells co-cultured with normal HPMCs also have reduced E-cadherin expression (Fig. 2). According to recent reports, CAFs are implicated in cancer by producing high quantities of stromal-derived factor-1α (SDF-1α), also known as chemokine CXCL12 (31); SDF-1α expression is higher in mesothelial cells than in other organs (32). Although we hypothesized that differences in SDF-1α expression may be responsible for the differential activity of HPMCs and a-HPMCs observed in our study, we found no evidence to support this (data not shown). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peritoneal dissemination is the most frequent metastatic pattern of scirrhous gastric cancer. However, despite extensive research effort, disease outcomes have not improved sufficiently. Tumor progression and metastasis result from interactions between cancer and various cells in the stroma, including endothelial cells, immune cells and fibroblasts. Fibroblasts have been particularly well studied; they are known to change into carcinoma-associated fibroblasts (CAFs) and produce transforming growth factor β (TGF-β), which mediates cancer-stroma interactions. Here, we investigated whether TGF-β derived from cancer cells in the peritoneal microenvironment activates human peritoneal mesothelial cells (HPMCs), leading to the progression and fibrosis of gastric cancer. We found that activated HPMCs (a-HPMCs) took on a spindle shape formation, decreased the expression of E-cadherin and increased that of α-SMA. Furthermore, a-HPMCs became more invasive and upregulated proliferation of human gastric cancer-derived MKN45 cells following direct cell-cell contact. Notably, MKN45 cells co-cultured with a-HPMCs also acquired anchorage-independent cell growth and decreased expression of E-cadherin in vitro. To measure the effects of the co-culture in vivo, we developed a mouse xenograft model into which different culture products were subcutaneously injected. The largest tumors were observed in mice that had been given MKN45 cells co-cultured with a-HPMCs. Furthermore, these tumors contained HPMC-derived fibrous tissue. Thus, the epithelial-mesenchymal transition (EMT) of HPMCs appears to drive peritoneal dissemination and tumor fibrosis.
    Full-text · Article · May 2012 · International Journal of Oncology
Show more